The minimum lifetime prevalence of psychiatric illnesses in the general population is 10%. The majority of all successful suicides are committed by persons who suffer from depression. The financial cost for treatment and loss of productivity is in the hundreds of millions of dollars each year. The biological cause(s) of these illnesses is mostly unknown. The ultimate aim of the proposed research is to identify a gene that causes the affective disorder phenotype. Affective Disorder (AD) is a term given to a group of illnesses of mood disturbance accompanied by manic and depressive syndrome. The results from twin and family studies suggest genetics plays a major, but complex, role in the etiology of AD. The bipolar affective disorder (manic-depression) that is present in the Old Order Amish (OOA) has a similar symptom pattern, clinical course and prevalence rate as is found in the general North American population. The OOA are among the best characterized and diagnosed psychiatric pedigrees. Segregation analysis suggests that in this genetic isolate AD is transmitted as an autosomal dominant trait, therefore the predisposition gene can be identified through family study. Linkage analysis with highly polymorphic microsatellite or candidate gene markers will be conducted to test the hypothesis of genetic linkage. We plan to adapt a semi-automated method to increase the throughput and decrease the error of genotyping. A systematic survey of the entire genome will be conducted to locate the susceptibility locus in this pedigree. Evidence for linkage will be sought using the bipolar I phenotype alone as well as bipolar II and major depressive disorder. The OOA pedigree is large enough to detect linkage using only the bipolar I phenotype and is therefore robust in the face of phenotypic heterogeneity. Once chromosome location is known, molecular methods utilizing somatic cell genetics, yeast artificial chromosome cloning and transcript isolation will be applied to identify the gene. In the future, knowledge of the gene's function may lead to a specific treatment of this illness formulated with respect to the pathways, neurons or transmitters that are affected or changed.